Multiple myeloma (MM) is a cancer of bone marrow plasma cells that results in over ten thousand deaths a year in the USA. For a while it responds well to treatment with DNA alkylators, glucocorticoids, proteasome inhibitors and the IMiD class of immunomodulators (thalidomide, lenalidomide and pomalidomide). All of these drugs can have profound effects on the immune system, and may interact either positively or negatively with different immunotherapies. Using the immunocompetent Vk*MYC genetically engineered mouse model of multiple myeloma we have noted marked in vivo but little in vitro anti-MM activity of SMAC-mimetic compounds (SMC), which we found activate the innate immune system causing a type I interferon dependent anti-tumor response. We have previously shown that response in this mouse model has a 68% positive predictive value for response in patients with MM. Based on these data we have intiated a phase II clinical trial in MM, and the first patients are responding to treatment. We propose to explore the combination of standard of care agents with SMC using the Vk*MYC mouse model to determine what properties of the former are synergistic or antagonistic for the combination. In parallel we will study the samples obtained from patients enrolled in the clinical trial. Preliminary studies suggest that these drugs are suppressing monocyte/macrophage secretion of inflammatory cytokines, and activating plasmacyoid dendritic cells to secrete interferon, resulting in MM cell death in vivo. The current proposal will use congenic tumor transplant models with selective immuno depletion, genetic depletion, and selecive add-back to precisely identify the host cells mediating the anti-MM effect in vivo and the effects of the combintaion with a standard of care agent. Finally we will analyze blood and bone marrow samples from MM patients treated on a phase II clinical trial of an IAP-antagonist to determine the immunologic sequelae of in vivo drug treatment. These studies will pave the way for the rational combination of standard of care agents with a new class of immunomodularity drugs for the treatment of multiple myeloma.